Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke Academic Article uri icon


MeSH Major

  • Connexin 43
  • Diabetes Mellitus, Experimental
  • Diabetic Retinopathy
  • Gap Junctions
  • Pericytes
  • Retinal Vessels


  • Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a┬ásingle dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

publication date

  • May 16, 2019



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2019.03.032

PubMed ID

  • 31056284

Additional Document Info

start page

  • 1262

end page

  • 1279.e25


  • 177


  • 5